The transdermal route of parenteral delivery of drugs provides many advantages over other administrative routes. Passive transdermal systems which deliver a wide variety of agents by the physical process of diffusion are described in U.S. Pat. Nos. 3,598,122; 3,598,123; 4,286,592; 4,314,557; 4,379,454 and 4,568,343, for example, all of which are incorporated herein by reference. A passive system in its simplest form consists of a polymeric reservoir having the agent to be delivered dispersed therethrough. The agent diffuses through the reservoir, across the reservoir-biological surface interface, and subsequently across the biological surface. When the biological surface is human skin, the stratum corneum layer of the skin is a complex barrier due to a chemical keratinphospholipid complex which acts along with the horny layer as a barrier to the penetration of drugs into the body. The stratum corneum is known to both a lipophilic phase as well as a hydrophilic phase. In general, passive drug delivery involves the diffusion of drugs through the lipophilic phase of the stratum corneum and the underlying layers of the skin. As used herein, the term "passive" is defined as meaning drug delivery by diffusion and without electrical assistance. The term "biological surface" as used herein, is defined as including without limitation, skin, mucosal membranes, nails and blood vessel walls. In general, it is preferable to passively deliver non-ionized drugs and agents using a passive transdermal delivery system since ionized drugs and agents usually are unable to passively permeate through human skin at therapeutically effective rates.
A more recent method of transdermal drug delivery uses electrical current to actively transport agents across a biological surface. This concept is based upon basic principles of electrochemistry and is referred to herein as electrically assisted or iontophoretic delivery. Abramson and Gorin in J. Phys. Chem. 44, pp 1094-1102 (1940) showed that charged ions can be introduced into the skin under the influence of an electric field and that the pathways for transdermal ion transport are hydrophilic pathways in the skin. These hydrophilic pathways include the sweat glands and a hair follicles. Thus, although both passive delivery devices and electrically-assisted delivery devices involve drug delivery through the skin, the transdermal pathways for drugs delivered from passive devices and electrically-assisted devices are quite different.
Iontophoresis, according to Dorland's Illustrated Medical Dictionary, is defined to be "the introduction, by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes."
Iontophoretic devices have been known since the early 1900's British patent specification No. 410,009 (1934) described an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be immobilized near such source. The device of that British specification was made by forming a galvanic cell from the electrodes and the material containing the medicament or drug to be delivered transdermally. The galvanic cell produced the current necessary for iontophoretically delivering the medicament. This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activities.
More recently, a number of U.S. patents have issued in the iontophoresis field, indicating a renewed interest in this mode of drug delivery. For example, Vernon et al U.S. Pat. No. 3,991,755; Jacobsen et al U.S. Pat. No. 4,141,359; Wilson U.S. Pat. No. 4,398,545; and Jacobsen U.S. Pat. No. 4,250,878 disclose examples of iontophoretic devices and some applications thereof. The iontophoresis process has been found to be useful in the transdermal administration of medicaments or drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and many other drugs. Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
In presently known iontophoretic devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by electromigration (ie, the movement of charged ions within an electric field imposed across the body surface). The other electrode, called the counter, indifferent, inactive or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be delivered into the body is positively charged (i.e., a cation), then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged (i.e., an anion), then the cathode will be the active electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anode can deliver a positively charged ionic substance into the body while the cathode can deliver a negatively charged ionic substance into the body.
It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electroosmosis. Electroosmosis is the transdermal flux of a liquid solvent (e.g., the liquid solvent containing the uncharged drug or agent) which is induced by the presence of an electric field imposed across the skin by the donor electrode. As used herein, the terms "iontophoresis" and "iontophoretic" refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
As with passive transdermal delivery systems, iontophoretic delivery devices also require a reservoir or source of the beneficial agent to be delivered into the body. In general, it is preferable to deliver ionized drugs and agents using an iontophoretic delivery device. Examples of such reservoirs or sources of ionized or ionizable agents include a pouch as described in the previously mentioned Jacobsen U.S. Pat. No. 4,250,878, or a pre-formed gel body as described in Webster U.S. Pat. No. 4,383,529 and Ariura et al. U.S. Pat. No. 4,474,570. Such drug reservoirs are electrically connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired agents.
More recently, iontophoretic delivery devices have been developed in which the donor and counter electrode assemblies have a "multi-laminate" construction. In these devices, the donor and counter electrode assemblies are formed of multiple layers of (usually) polymeric matrices. For example, Parsi U.S. Pat. 4,731,049 discloses a donor electrode assembly having hydrophilic polymer based electrolyte reservoir and drug reservoir layers, a skin-contacting hydrogel layer, and optionally one or more semipermeable membrane layers. Sibalis U.S. Pat. No. 4,640,689 discloses in FIG. 6 an iontophoretic delivery device having a donor electrode assembly comprised of a donor electrode (204), a first drug reservoir (202), a semipermeable membrane layer (200), a second drug reservoir (206), and a microporous skin-contacting membrane (22'). The electrode layer can be formed of a carbonized plastic, metal foil or other conductive films such as a metallized mylar film. In addition, Ariura et al, U.S. Pat. 4,474,570 discloses a device wherein the electrode assemblies include a conductive resin film electrode layer, a hydrophilic gel reservoir layer, a current distribution and conducting layer and an insulating backing layer. Ariura et al disclose several different types of electrode layers including an aluminum foil electrode, a carbon fiber non-woven fabric electrode and a carbon-containing rubber film electrode.
Transdermal iontophoretic delivery devices having electrodes composed of electrochemically inert materials, as well as devices having electrodes composed of electrochemically reactive materials are known. Examples of electrochemically inert electrode materials include platinum, carbon, gold and stainless steel. The prior art has also recognized that the electrochemically reactive electrode materials are in many cases preferred from the standpoint of drug delivery efficiency and pH stability. For example, U.S. Pat. Nos. 4,744,787; 4,747,819 and 4,752,285 all disclose iontophoretic electrodes composed of materials which are either oxidized or reduced during operation of the device. Particularly preferred electrode materials include silver as the anodic electrode, and silver chloride as the cathodic electrode.
A primary advantage of passive transdermal delivery systems over electrically assisted iontophoretic delivery devices is cost. Because passive systems do not require any source of electrical power and the attendant electrical circuitry, the cost of a passive system is significantly less than an electrically powered iontophoretic delivery device adapted to deliver the same drug. Passive systems are also typically much easier to manufacture in part because of their simpler construction and lack of any electrical components. On the other hand, passive systems can only be used to deliver those drugs which are able to permeate through skin at pharmacologically effective rates. Because human skin presents a significant barrier to passive drug permeation, relatively few drugs have been found to be suitable for passive delivery systems.
Electrically assisted iontophoretic delivery devices on the other hand have the ability to deliver many drugs at therapeutically effective rates, including drugs having high molecular weights such as polypeptides and proteins, which cannot be delivered at therapeutically effective rates by passive transdermal delivery systems. In addition, electrically assisted iontophoretic delivery devices provide other advantages over passive transdermal delivery systems. One advantage is the shorter time required to reach pharmacologically effective transdermal drug delivery rates. Electrically assisted devices can achieve pharmacologically effective transdermal delivery rates within several minutes of start-up whereas passive transdermal delivery systems typically require much longer start-up periods. A second advantage of electrically assisted iontophoretic delivery devices is the degree of control over the amount and rate of drug delivered from the device, which can be achieved simply by controlling the level of electrical current applied by the device. A third advantage of electrically-assisted iontophoretic delivery devices is their ability to be programmed to deliver drug at a predetermined regimen and their ability to deliver either a bolus dose or to deliver medication "on demand" in applications such as the delivery of narcotic analgesics for treatment of pain. Passive transdermal delivery systems do not have these active control features and simply deliver drug at a rate predetermined by the design of and the materials used in, the passive system.
It is therefore an object of this invention to provide a transdermal delivery device having the advantages of a passive transdermal delivery system and the advantages of an electrically assisted iontophoretic delivery device.
In particular, it is an object of the present invention to provide a transdermal delivery device, at least a portion of which is electrically powered and capable of delivering an agent transdermally by iontophoresis, and therefore able to deliver drugs transdermally at therapeutically effective rates with a minimal start-up time and in preprogrammed or on demand delivery regimens.
It is a further object of the present invention to provide a transdermal agent delivery device, at least a portion of which delivers drugs transdermally by passive non-electrically assisted delivery and which is able to deliver agent without consuming electrical power.